1ogs



Human acid-beta-glucosidase (see also Treatment of Gaucher disease)



Overview
Gaucher disease, the most common lysosomal storage disease, is caused by mutations in the gene that encodes acid-beta-glucosidase (E.C. 3.2.1.45, GlcCerase). Type 1 is characterized by hepatosplenomegaly, and types 2 and 3 by early or chronic onset of severe neurological symptoms. The correlation between the ~ 200 mutations in GlcCerase and disease severity is not completely understood, although homozygosity for the common mutations N370S and L444P is associated with non-neuronopathic and neuronopathic disease, respectively. The X-ray structure of GlcCerase at was resolved at 2.0 A resolution. The catalytic domain consists of a (beta/alpha)(8) TIM barrel, as expected for a member of the glucosidase hydrolase A family. The distance between the catalytic residues E235 and E340 is consistent with a catalytic mechanism of retention. N370 is located on the longest alpha-helix (helix 7 ), which has several other mutations of residues that point into the TIM barrel. Helix 7 is at the interface between the TIM barrel and a separate immunoglobulin-like domain on which L444 is located, suggesting an important regulatory or structural role for this non-catalytic domain. The structure provides the possibility of engineering improved GlcCerase for enzyme-replacement therapy, and for designing structure-based drugs aimed at restoring the activity of defective GlcCerase

About this Structure
1OGS is a Single protein structure. Full crystallographic information is available from OCA.

Reference
X-ray structure of human acid-beta-glucosidase, the defective enzyme in Gaucher disease., Dvir H, Harel M, McCarthy AA, Toker L, Silman I, Futerman AH, Sussman JL, EMBO Rep. 2003 Jul;4(7):704-9. PMID:12792654

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